Summary of Work: The goal of this work is to identify and characterize dietary/nutrient factors and regimens that modulate the expression of environmentally induced oxidative stress in normal and diseased states. Work to date has focused specifically on one important aspect of the diet --calories. We have shown thatcalorie restriction mitigates chemical induced oxidative stress in three animal models: ozone-induced lung inflammation, dust-mite induced allergy and oxazalone induced delayed contact hypersensitivity in skin. Furthermore, in all cases, functional challenges of ex vivo preparations mirror the inherent desensitization observed in vivo . For example, compared to ad lib fed animals, calorie restricted rats exposed to equivalent concentrations of inhaled ozone respond with decreased total protein, IL-6, and fibronectin accumulation in the bronchoalveolar lavage fluid (BAL) and decreased polymorphonuclear cell (PMN) infiltration 24 hours after the ozone challenge. Subsequent challenge to aerosolized bacteria show that feed restricted animals phagocytosized much more efficiently than the ad lib animals. Furthermore, pulmonary macrophages harvested from calorie restricted rats respond to endotoxin challenges with decreased production/secretion of pro-inflammatory cytokines such as TNF, IL-6, and nitric oxide. Analogous experiments conducted with ad libitum-fed vs feed restricted Balb/C mice revealed markedly decreased ear swelling following topical application of oxazolone to the restricted animals. This indicates depressed oxidative stress in vivo. Local lymph node preparations from restricted mice exhibit a depressed response to mitogen stimulated T-cell proliferation. Thus, in these animal models, the ex vivo preparations have been preconditioned by their in vivo nutritional environment and they "remember" these conditions long enough to respond differentially ex vivo. This work is significant because it suggests that there are energy-related set-points which amplify/attenuate environmental stresses. The fact that this is observed in three unrelated exposure models indicates that this is likely to be a general phenomenon.